Although a variety of foods are abundant in folate vitamers, the dietary habits, the varied bioavailabilities of food folates and the losses of folates during processing, storage and preparation make it uncertain to achieve the recommended folate intake for the general populations. Therefore, food fortification and/or supplements of folates are recommended, especially for females of childbearing age. As folic acid has better stability and bioavailability compared to natural folate vitamers, it is commonly utilised in fortified foods and supplements. Folic acid becomes biologically active in the cells via a series of enzymatic reactions, starting with the reductions to DHF and then to THF followed by further conversions to 5-CH3-THF and sometimes to 10-CHO-THF during transports through the gut mucosa (Scott et al. 2000).
2.4.1 Benefits
Neural tube defects are serious congenital malformations due to failure of closure of the covering of the brain or spinal cord during early development stages of the embryo, mainly
including birth defects anencephaly and spina bifida. As the neural tube forms during the 18-20th day of pregnancy and closes during the 24-27th day, the interventions should occur at least one month before conception until the first six weeks of pregnancy. In a number of trials and case studies, preconceptional intervention with folic acid showed strongly preventive effects against NTDs with significant reductions of 50-72% (Molloy 2005;
Pitkin 2007).
Mandatory fortification of folic acid has been conducted in more than fifty countries, recommending an additional intake of 400 μg folic acid/d for women that are planning or capable of becoming pregnant. The effectiveness of the folic acid supplement used in potential pregnant women has been investigated in some countries, showing a decline in NTDs by 8% in New Zealand, 12% in Austrialia, and 20-30% in the US (Pitkin 2007;
Dalziel et al. 2010).
2.4.2 Adverse effects
No adverse effects have been observed from excess consumption of folates from foods. On the other hand, although no toxicological information has been related to the use of synthetic folic acid, some adverse effects have been reported for folate fortification and supplementation. The FDA set a safe upper limit of 1 mg folate/d for the intakes from fortified foods and dietary supplements, and required a health claim for exceeding this level (FDA 1996).
Masking of vitamin B12 deficiency symptoms
Since folates and vitamin B12 are interrelated cofactors in the remethylation of homocysteine, vitamin B12 deficiency can result in the entrapment of 5-CH3-THF and the resulting inavailablity of 5,10-CH2-THF coenzyme for thymidine formation, which develops a secondary folate deficiency (SCF 2000) (Figure 2). Thus, insufficient supply of either folates or vitamin B12 can lead to changes of the megaloblasts in the bone marrow and other replicating cells owing to disabled DNA synthesis. For people having a deficiency of vitamins B12, the administration of folic acid brings new supply of 5,10-CH2 -THF, thereby repairing DNA synthesis and remitting haematological symptoms. Even a small dosage of 0.1 mg folic acid/day to patients with pernicious anaemia may restore normoblastic erythropoiesis and, thereby, suppress anaemic symptoms (Dickinson 1995).
If undiagnosed anaemia is masked by the supplement of folic acid, further development of neurological deterioration is most likely to take place. According to a large number of studies, though treatment with folic acid could correct the vitamin B12-derived anaemia; it did not prevent, but might allow and even precipitate neurological relapses, especially posterolateral spinal cord disease and peripheral neuritis. Although the theory of effects of folic acid is still not clear, it may reduce the plasma vitamin B12 level or disturb vitamin B12 metabolism, thereby exacerbating neurological damages (Dickinson 1995).
Figure 2. Overview of how folic acid fortification and supplements mask a vitamin B12 deficiency; DHF:
dihydrofolate, THF: tetrahydrofolate, 5-CH3-THF: 5-methyltetrahydrofolate, 5,10-CH2-THF: 5,10-methylenetetrahydrofolate, 10-CHO-THF: 10-formyltetrahydrofolate, SAM: adenosylmethionine, SAH: S-adenosylhomocysteine (Houghton et al. 2006).
Effects on zinc absorption and deficiency
In a human study, a marginal diet of zinc and 400 μg folic acid/d led to an increased fecal zinc level and a decreased urinary excretion of about 50% (Milne et al. 1984). Moreover, a 30% decrease in the zinc absorption was found in adults receiving folic acid supplement
(800 μg) (Milne 1989). Folic acid may chelate intestinal zinc to form unabsorbable complex and inhibit the transport of Zn in the lumen, thereby decreasing zinc bioavailability (Keating et al. 1987).
In addition, it has been reported that superimposition of the deficiencies in both zinc and folates may increase the incidence of abnormal morphogenesis in rat embryos (Bremert et al. 1989). In an animal study, rats with zinc deficiency were unable to convert folic acid to the metabolically active form, so the researchers concluded that teratogenesis of these subjects was possibly increased by folic acid supplementation (Quinn et al. 1990).
Neurotoxicity
There is no consistent evidence for possible neurotoxicity of folic acid in humans. Some animal studies have shown that folic acid exhibited neurotoxic and epileptogenic effect at very high dose levels (60-90 mg). Hunter et al. (1970) reported the development of gastrointestinal and/or nervous toxicity in healthy people after an oral administration of 15 mg folic acid/d. Meanwhile, some healthy volunteers developed gastrointestinal, neurological and psychological abnormalities in a month when receiving 5 mg of folic acid three times a day. But such results were inconsistent with other better-planned studies (Campbell 1996).
Carcinogenicity
Some animal and human studies have shown some evidences that a high level of folate intake from supplements and/or fortification might cause a paradoxical promotion of carcinogenicity among individuals who harboured neoplastic foci. In addition, Farber et al.
(1947) reported that the administration of folic acid conjugates to patients with acute leukemia accelerated the leukemic progression. On the contrary, a folic acid antagonist, aminopterin, brought about temporary remissions in 5 out of 16 children suffering acute leukemia (Farber et al. 1948). Moreover, a promoting effect towards breast cancer has also been observed among postmenopausal women taking folic acid supplements above the level of 853 mcg/d, while a reduction of >40% in the risk of breast cancer was observed for decreasing dietary intakes of folates (Ulrich 2007; Mason 2009). In a follow-up study on the carcinogenicity of prescription drugs, folic acid showed an increasing effect on the
incidence of cancers of oropharynx, hypopharynx and so on, but the intervention of factors, such as smoking and drinking, could not be ruled out (Selby et al. 1989).
Meanwhile, it has been known that oral administrations of folic acid could saturate the conversion pathway of folic acid into bioactive forms, thereby leading to detectable levels of unmetabolised folic acid in the plasma. Increased plasma levels of folic acid have been inversely related with the decreases in the cytotoxicity of circulating natural killer cells, which acted on the destruction of growing colons of neoplastic cells (Mason 2009).
On the other hand, a great number of epidemiological and clinical studies have suggested an inverse relationship between folate status and colon cancer risk, but the dose and timing of folate supplementation seem to be critical for a safe and effective prophylaxis. It appeared that high doses of supplemental folates (>20 times of the basal daily dietary requirement) and intervention after neoplastic foci did not produce preventive effects but, in some cases, enhanced colorectal carcinogenesis (Kim 2004). Meanwhile, a folate-deficient diet was shown to significantly decrease the incidence of adenocarcinomas and tumors in small intestine, but not adenomas and large intestinal tumors (Kim 2003).
Effects on antifolate drugs
A number of folate antagonists have been used in antifolate therapies, including methotrexate, pyrimethamine, phenytoin, clochicine, etc. Because of their abilities to suppress the growth of malignant tumors, some antifolate drugs are used to enhance cancer-fighting effects or to protect healthy cells in treatments of various cancers, e.g.
leukemia, non-Hodgkin’s lymphoma, breast cancer, bladder cancer. Other diseases employing antifolate medications include rheumatoid arthritis, bronchial asthma, psoriasis, bacterial infections and so on (SCF 2000). The antifolate drugs can directly interfere with folic acid metabolism. On the other hand, folic acid supplement may decrease patients’
serum level of phenytoin−a commonly-used antiepileptic, and may consequently increase seizure frequency. Furthermore, the methotrexate efficacy in rheumatoid arthritis treatment might be reduced by high doses of folinic acid (Campbell 1996).